This is an application for a K01 Mentored Research Scientist Development Award entitled "Influence of Gonadal Hormones on Fear Extinction." Rodent and human neuroimaging studies indicate that the ventral medial prefrontal cortex (vmPFC) is critical for extinction memory recall. The candidate will use functional MRI and psychophysiological measures to examine the influence of sex and variance of gonadal hormones on the functional activity of brain regions involved in extinction recall. Two hypotheses will be tested: 1) elevated estrogen levels during menstrual cycle will attenuate functional activity of the extinction circuit, specifically vmPFC, and thus extinction capacity will be reduced, and 2) administration of progesterone will facilitate functional activity of this extinction circuitry during extinction recall that will result in enhanced extinction capacity. To test these hypotheses, healthy human volunteers will undergo a two-day fear conditioning and extinction protocol while measuring brain responses using fMRI. Skin conductance responses will be measured and used as an index of fear. The resources for the proposed research are provided by Massachusetts General Hospital (MGH) Psychiatric Neuroimaging Research Program, the MGH/MIT/HMS Athinolas A. Martinos Center for Biomedical Imaging, and the MGH/MIT General Clinical Research Center. The immediate objective of the candidate is to obtain in-depth training in functional MRI, cognitive neuroscience, and neuroendocrinology and to enhance skills in research and ethics. The long-term career goal is for the candidate to become an established investigator with expertise to study the influence of gonadal hormones on brain function during processing of emotional stimuli. Relevance: The prevalence of anxiety disorders, characterized by increased fear, is twice as high in women relative to men. This proposal will begin to examine the neurobiological basis for these differences by first studying how healthy men and women may differ in learning not to fear. The experiments herein will investigate the influence of hormonal changes (i.e. estrogen and progesterone) during different phases of the menstrual cycle on the activity of brain regions involved in signaling memory for safety. This proposal will also examine the influence of progesterone administration on boosting the brain's signal for safety. Findings from this proposal may help the development of sex-specific treatments for anxiety disorders.[unreadable]